The following discussion of the background of the invention is merely provided to aid the reader in understanding the invention and is not admitted to describe or constitute prior art to the present invention.
A stroke is a sudden interruption in the blood supply of the brain. Most strokes are caused by an abrupt blockage of arteries leading to the brain (ischemic stroke). Other strokes are caused by bleeding into brain tissue when a blood vessel bursts (hemorrhagic stroke). Because stroke occurs rapidly and requires immediate treatment, stroke is also called a brain attack. When the symptoms of a stroke last only a short time (less than an hour), this is called a transient ischemic attack (HT) or mini-stroke. Stroke has many consequences.
The effects of a stroke depend on which part of the brain is injured, and how severely it is injured. A stroke may cause sudden weakness, loss of sensation, or difficulty with speaking, seeing, or walking. Since different parts of the brain control different areas and functions, it is usually the area immediately surrounding the stroke that is affected. Sometimes people with stroke have a headache, but stroke can also be completely painless. It is very important to recognize the warning signs of stroke and to get immediate medical attention if they occur.
Stroke or brain attack is a sudden problem affecting the blood vessels of the brain. There are several types of stroke, and each type has different causes. The three main types of stroke are listed below.
Ischemic stroke is the most common type of stroke—accounting for almost 80% of strokes—an is caused by a clot or other blockage within an artery leading to the brain.
Intracerebral hemorrhage is a type stroke caused by the sudden rupture of an artery within the brain. Blood is then released into the brain, compressing brain structures.
Subarachnoid hemorrhage is also a type of stroke caused by the sudden rupture of an artery. A subarachnoid hemorrhage differs from an intracerebral hemorrhage in that the location of the rupture leads to blood filling the space surrounding the brain rather than inside of it.
Ischemic stroke occurs when an artery to the brain is blocked. The brain depends on its arteries to bring fresh blood from the heart and lungs. The blood carries oxygen and nutrients to the brain, and takes away carbon dioxide and cellular waste. If an artery is blocked, the brain cells (neurons) cannot make enough energy and will eventually stop working. If the artery remains blocked for more than a few minutes, the brain cells may die. This is why immediate medical treatment is absolutely critical.
Ischemic stroke can be caused by several different kinds of diseases. The most common problem is narrowing of the arteries in the neck or head. This is most often caused atherosclerosis, or gradual cholesterol deposition. If the arteries become too narrow, blood cells may collect and form blood clots. These blood clots can block the artery where they are formed (thrombosis), or can dislodge and become trapped in arteries closer to the brain (embolism). Another cause of stroke is blood clots in the heart, which can occur as a result of irregular heartbeat (for example, atrial fibrillation), heart attack, or abnormalities of the heart valves. While these are the most common causes of ischemic stroke, there are many other possible causes. Examples include use of street drugs, traumatic injury to the blood vessels of the neck, or disorders of blood clotting.
Ischemic stroke can further be divided into two main types: thrombotic and embolic.
A thrombotic stroke occurs when diseased or damaged cerebral arteries become blocked by the formation of a blood clot within the brain. Clinically referred to as cerebral thrombosis or cerebral infarction, this type of event is responsible for almost 50% of all strokes. Cerebral thrombosis can also be divided into an additional two categories that correlate to the location of the blockage within the brain: large-vessel thrombosis and small-vessel thrombosis. Large-vessel thrombosis is the term used when the blockage is in one of the brain's larger blood-supplying arteries such as the carotid or middle cerebral, while small-vessel thrombosis involves one (or more) of the brain's smaller, yet deeper penetrating arteries. This latter type of stroke is also called a lacuner stroke.
An embolic stroke is also caused by a clot within an artery, but in this case the clot (or emboli) was formed somewhere other than in the brain itself. Often from the heart, these emboli will travel the bloodstream until they become lodged and cannot travel any further. This naturally restricts the flow of blood to the brain and results in almost immediate physical and neurological deficits.
Thrombolytic therapy has been proven to be effective for the treatment of acute ischemic stroke, but the increased risk of tissue plasminogen activator (tPA) is still of great clinical concern (see for instance The National Institutes of Neurological Disorders, and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. New England Journal of Medicine 1995;333:1581-7).
As it is critical to restore proper blood flow to the brain as soon as possible to prevent tissue damage, rapid diagnosis of stroke is critical to the survival of the patient and the minimization of any effects of the stroke to the patient. If caught from three to six hours after occurrence most stroke patients can expect full or parHTI recovery
Current state of the art diagnosis of stroke involves a physical examination and imaging procedures such as computed tomography (CT) scan, angiogram, electrocardiogram, magnetic resonance imaging (MRI), Single photon emission computed tomography (SPECT) and positron emission tomography (PET).
While physical examination is rapid, it only can detect large strokes (defined to be significant impairment of symptoms on the National Institutes of Health Stroke Scale, (NIHSS) of greater than 12). In addition, prior studies have found that the accuracy of stroke identification by medical personnel is modest and variable from one community to another. Sensitivity for stroke recognition by prehospital personnel has ranged widely, and positive predictive values have remained between 64% and 77% (see for instance Zweifler R M, York D, U T T, Mendizabal J E, Rothrock J F. Accuracy of paramedic diagnosis of stroke. J Stroke Cerebrovasc Dis. 1998;7:446-448.). These studies have consistently suggested a tendency for prehospital personnel to overdiagnose stroke by not recognizing stroke mimics, such as patients with alcohol and drug intoxication, postictal hemiparesis, hypoglycemia or other metabolic encephalopathies, and other nonstroke causes of acute neurological deficits. Finally, any clinical neurological screening test will be limited by the training and experience of the examiner. This suggests the need for an adjunctive clinical test that can provide diagnostic information above and beyond screening clinical exams.
CT scan produces x-ray images of the brain and is used to determine the location and extent of hemorrhagic stroke. It has widespread availability. CT scan usually cannot produce images showing signs of ischemic stroke until 48 hours after onset. This insensitivity to acute stroke limits its use to post-stroke damage assessment.
SPECT and PET involve injecting a radioactive substance into the bloodstream and monitoring it as it travels through blood vessels in the brain. These tests allow physicians to detect damaged regions of the brain resulting from reduced blood flow. However, this takes several hours, and thus is not used for rapid diagnosis of stroke.
MRI with magnetic resonance angiography (MRA) uses a magnetic field to produce detailed images of brain tissue and arteries in the neck and brain, allowing physicians to detect small-vessel infarct (i.e., stroke in small blood vessels deep in brain tissue). However, as a practical issue, most hospitals do not have these specialized and highly expensive MRI services available in the acute setting. Thus, without a practical and widely available radiological test, the diagnosis of stroke remains largely a clinical decision.
Thrombolytic therapy has been proven to be effective for the treatment of acute ischemic stroke, but the increased risk of hemorrhagic transformation (HT) associated with tissue plasminogen activator (tPA) administration is still of great clinical concern. HT after cerebral ischemia seems to be related to the disruption of the vascular endothelium (see for instance Hamann G F, Okada Y, del Zoppo G J. Hemorrhagic transformation and microvascular integrity during focal cerebral ischemia/reperfusion. J Cereb Blood Flow Metab. 1996;16:1373-1378.). In patients who receive tPA treatment, endothelial injury may be the result of free radical generation secondary to thrombolytic-induced reperfusion (see for instance), as well as of the upregulation of matrix metalloproteinases (MMPs) (see for instance Lapchak P A, Chapman D F, Zivin J A. Pharmacological effects of the spin trap agents N-t-butyl-phenylnitrone (PBN) and 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) in a rabbit thromboembolic stroke model: combination studies with the thrombolytic tissue plasminogen activator. Stroke. 2001;32:147-152.), a group of enzymes that are able to degrade the basal membrane components. The association between high levels of MMP-9 and the risk of HT in patients with acute ischemic stroke who have and have not received tPA have been previously reported (see for instance Sumii T, Lo E H. Involvement of matrix metalloproteinase in thrombolysis-associated hemorrhagic transformation after embolic focal ischemia in rats. Stroke. 2002;33:831-836.; Montaner J, Molina C A, Monasterio J, Abilleira S, Arenillas J F, Ribo M, Quintana M, Alvarez-Sabin J. Matrix metalloproteinase-9 pretreatment level predicts intracranial hemorrhagic complications after thrombolysis in human stroke. Circulation. 2003;107:598-603.). However, despite the available data, the underlying molecular mechanisms related to HT after thrombolytic treatment have yet to be fully elucidated.
Accordingly, there is a present need in the art for a rapid, sensitive and specific differential diagnostic assay for stroke, stroke subtype, and stroke mimic that can also identify those individuals at risk for hemorrhagic transformation after presentation with stroke symptoms and subsequent administration of tPA therapy. Such a diagnostic assay would greatly increase the number of patients that can receive beneficial stroke treatment and therapy and in so doing reduce the costs associated with incorrect stroke diagnosis. Some content of this patent application was first published in the journal Stroke in its May 27, 2004, electronic issue.